ELF- magnetic field and immune response modulation WM proposal as - - PowerPoint PPT Presentation

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

ELF- magnetic field and immune response modulation

1AIT Austrian Institute of Technology GmbH, Tulln, Austria 2Neiding BV, Wageningen, Netherland 3CNRS, Institut Gustave-Roussy, UMR 8203, Villejuif F-94805, France

WM proposal as an umbrella activity

Myrtill Simkó1, Mats-Olof Mattsson1, Jan Cuppen2, Luis Mir3,

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

Situation: ELF-EMF interacts with biological systems! Fact: Different cell types react differently since they have different homeostatic capacity! Hypothesis 1: ELF-EMF modulates oxidative response(s) dose (flux density and time) dependently Hypothesis 2: This modulation can be used positively.

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

Monocyte / Macrophage activation

JAK-STAT cascade

ROS

cytokine expression IL2 receptor

ELF-MF

cytokine signaling resolving inflammation cell proliferation angiogenesis ECM construction receptor X IL10 (IL20) receptor

a b

IL15 receptor

a b 

MAPK cascade

FOS O2 O-

2 IL2 IL10 IL15 IL2 IL10 IL15

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

Alternative activation pathway

Classically activated macrophages: PROMOTES:

inflammation extracellular matrix (ECM) destruction apoptosis

phagocytosis → oxidative burst tends to elicit chronic inflammation and tissue injury Alternatively activated macrophages: PROMOTES:

cell proliferation ECM construction angiogenesis

pinocytosis → free radical release tends to resolve inflammation and facilitate wound healing

Antigen-presenting phagocytes, secrete pro-inflammatory and antimicrobial mediators Lectine dependent activation

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

Summary of own results

 EMF induce immune cell activation: ROS, IL-1ß, phagocytosis, HSP70  Seems to be cell type specific responses (different redox status, specific physiologic function), not in a general way  ROS and HSP70 production: dose independency (flux density, time)  Radical scavengers inhibit ROS and HSP70  Modulation of the redox homeostasis leads to the activation of the alternative pathway in immune relevant cells

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

Summary and objectives

• The interface between physics and biology is still unclear
• It might be on the membrane, on receptor(s) or at other cell organell(s), and/or in

parallel

• MF modulation of cell specific oxidative responses may be depending on the

cell´s metabolic state and redox potential state

• It is known that MF influence different medical related processes such as

transcranial stimulation by MF, wound and bone healing, etc.

• There is a need to identify new areas of application (dental area: gingiva) and
• to specify targeted (optimization of exposure parameters) applications

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

The module goal

..is to focus on beneficial effects related to oxidative responses and modulation of immune system functions of EMF MF in order to 1) provide a better understanding of underlying physical and biological modes of action and 2) to contribute to the development of innovative EMF- based medical treatment.

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

Low-frequency electromagnetic field exposure enhances extracellular trap formation by human neutrophils through the NADPH-pathway (accepted)

Golbach LA, Scheer MH, Cuppen JJM, Savelkoul HFJ, Verburg-Van Kemenade BML

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

Conclusion

This is the first study to show that LF EMF exposure is able to enhance NET formation ex vivo. An increased NET formation of ~25% could be measured at four hours after stimulation with PMA. Cellular activation was needed, since LF EMF exposure alone was not able to promote NET formation. The pathways involved in PMA stimulated NET formation are partly known [29] and with the use of a selective pharmacological inhibitor we demonstrated that the NADPH- pathway is crucial for LF EMF enhanced NET formation, possibly by upregulated ROS production. These data provide a basic mechanism of action

• n immune cells to explain potential health effects of LF EMFs generated by

household appliances and power lines.

Low-frequency electromagnetic field exposure enhances extracellular trap formation by human neutrophils through the NADPH-pathway (accepted)

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

In vivo electroporation and immune response

• C. Y. Calvet, F. M. André and L. M. Mir

In vivo electroporation: not only an enhancer of gene transfer but also an adjuvant for DNA vaccination

Oncoimmunology 2014; 3:e28540; http://dx.doi.org/10.4161/onci.28540 (Point of View)

 ATP release: autophagy « find me » signal for dendritic cells IL-1β production  activation of IL-17+ γδ T cells and CD8+ T cells Favors DC differentiation and maturation  Exposure of Calreticuline (CRT): ER stress « eat-me » signal for dendritic cells  HMGB1 release: membrane disruption Pro-inflammatory cytokine Favors cross-presentation of tumor antigens by DCs ( Kroemer, 2013)

• C. Y. Calvet, D. Famin, F. M. André and L. M. Mir - Electrochemotherapy with bleomycin induces

hallmarks of immunogenic cell death in murine colon cancer cells. OncoImmunology 2014; 3:e28131; http://dx.doi.org/10.4161/onci.28131

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

However, no electroporation with EMF

No cell electroporation has been detected when cells are exposed to EMF HOWEVER:

• No cell electroporation so far proved with classical electroporation markers

does not means that nothing happens (ongoing molecular dynamics studies)

• ATP is a very small molecule: is it released?
• Moreover we already showed that there is an increase in endocytosis rate

that we consider (M. Breton, A. Silve and L.M. Mir, in preparation) as a late consequence of the membrane changes occurring during cell membrane electropermeabilization (whatever the level of electropermeabilization) => exposure of calreticulin?

• N. Mahrour, R. Pologea-Moraru, M. G. Moisescu, S. Orlowski P. Lévêque and L. M. Mir

In-vitro increase of the fluid phase endocytosis induced by pulsed radiofrequency electromagnetic fields : importance of the electric field component. Biochimica Biophysica Acta – Biomembranes, 1668, 126-137, 2005

• M. G. Moisescu, P. Leveque, M.-A. Verjus, E. Kovacs and L. M. Mir

900MHz modulated electromagnetic fields accelerates the clathrin-mediated endocytosis pathway Bioelectromagnetics 30, 222-230, 2009.

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

Moreover, besides potential calreticulin exposure and potential ATP release,

• ther avenues can be explored:

Indeed, it has been found by several groups (Teissié’s group, 1998, Pakhomov’s group, 2012) that ROS appear in the vicinity of the cells exposed to electric pulses... => the links to Myrtill’s hypothesis #1 and own data, as well as to Jan’s data must be explored ! An overall consistency seems to emerge from our three groups data and ideas Join us in a WM  ! or in several WMs   

4-6. March 2015, COST EMF-MED 3nd MCM, 2st WGMs Madrid, Spain

“Umbrella” activity for many WMs

Mode of action:

• Modulation of free radical

homeostasis

• Different endpoints with modest

effects

• Results from medical processes

(wound and bone healing, etc.)

• Development of targeted (E)MF

application:

• WG1
• WG2
• WG3